The artificial sweetener 4,1',6'-trichloro-4,1',6'-trideoxy-galactosucrose ("sucralose") is derived from sucrose by replacing the hydroxyls in the 4, 1' and 6' positions with chlorine. In the process of making the compound, the stereo configuration at the 4 position is reversed. Therefore, sucralose is a galacto-sucrose having the following molecular structure: ##STR1##
The direction of the chlorine atoms to only the desired positions is a major synthesis problem because the hydroxyls that are replaced are of differing reactivity; two are primary and one is secondary. The synthesis is further complicated by the fact that the primary hydroxyl in the 6 position is unsubstituted in the final product.
A number of different synthetic routes for the preparation of sucralose have been developed in which the reactive hydroxyl in the 6 position is first blocked, as by an ester group, prior to the chlorination of the hydroxyls in the 4, 1' and 6' positions, followed by hydrolysis to remove the ester substituent to produce sucralose. Several of such synthesis routes involve tin-mediated syntheses of sucrose-6-esters. Illustrative are the tin-mediated routes disclosed by Navia (U.S. Pat. No. 4,950,746), Neiditch et al. (U.S. Pat. No. 5,023,329), Walkup et al. (U.S. Pat. No. 5,089,608- "Walkup et al.-I"), Vernon et al. (U.S. Pat. No. 5,034,551), and Sankey et al., U.S. patent application Ser. No. 08/237,947, filed May 2, 1994, and assigned to the same assignee as this application.
The sucrose-6-esters produced by the above-cited synthesis routes are typically chlorinated by the process of Walkup et al., U.S. Pat. No. 4,980,463 ("Walkup et al.-II"). The chlorination process produces as a product a sucralose-6-ester, such as 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose-6-acetate ("TGS-6-Ac", when the sucralose-6-ester is the acetate ester, or, more generally, "TGS-6-ester") in solution in a tertiary amide, typically N,N-dimethylformamide ("DMF"), plus salts (produced as a result of neutralizing the chlorinating agent after completion of the chlorination reaction), and impurities. In one aspect, the present invention provides a process for the recovery of the TGS-6-ester from the solution in tertiary amide that is the product of the chlorination process of Walkup et al.-II.
In previous processes that have been disclosed, such as the processes disclosed in Walkup et al.-II and the process disclosed in Navia et al., "RECOVERY OF SUCRALOSE INTERMEDIATES", U.S. patent application Ser. No. 08/198,744, filed Feb. 18, 1994 (and re-filed on Jan. 1, 1995, as U.S. patent application Ser. No. 08/368,466), and assigned to the same assignee as this application, sucralose is produced from the chlorination reaction mixture of Walkup et al.-II by the following procedure:
a. after the neutralization step, the tertiary amide reaction vehicle for the chlorination reaction is removed, as by steam distillation (disclosed in Navia et al.), which forms an aqueous mixture containing salts, TGS-6-ester and impurities; PA1 b. the TGS-6-ester is then recovered from the aqueous mixture by extraction using a suitable organic solvent, such as ethyl acetate; PA1 c. the crude TGS-6-ester is then de-acylated to form sucralose; and PA1 d. the sucralose is recovered by counter-current extraction and purified by crystallization. PA1 1. Reduction of solids handling steps in the overall process, in that TGS-6-Ac is not discretely isolated. This effectively reduces the equipment needed (e.g., less need for centrifuges used for separation of solids from liquids); PA1 2. Probable reduction in the need to re-crop mother liquors (i.e., fewer re-crystallization steps). This is because crystallization of sucralose seems to be easier than crystallization of sucralose-6-acetate; and PA1 3. Overall yields appear to be increased slightly. This may be due to the conversion of diacetates that have the correct chlorination substitution to sucralose. These diacetates would be lost in the Navia et al. process because of the rigorous purification of TGS-6-Ac in Navia et al. PA1 (i) deacylating the 6-O-acyl-4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose, to produce an aqueous solution comprising sucralose, (b) salt including alkali metal or alkaline earth metal chloride, and (d) other chlorinated sucrose by-products; and PA1 (ii) recovering sucralose from the product of step (i), as by extraction followed by crystallization or by extractive techniques alone.
The present invention provides a process whereby the TGS-6-ester is de-acylated directly, to produce an aqueous solution of sucralose plus salts and impurities, from which sucralose is recovered, as by extracting with an organic solvent, and preferably the sucralose is then purified by counter-current extraction, crystallization or a combination of both techniques.
The process of this invention has several potential economic advantages over sucralose processes described before, e.g., the process disclosed in Navia et al., Ser. No. 08/368,466. These include the following: